Chronic (heavy) consumption of alcohol has been recognized as a major contributing factor in the pathogenesis of many vascular diseases, including diseases of the brain. A large body of evidence suggests that chronic consumption of alcohol predisposes to the development of both hemorrhagic and thromboembolic stroke. Mechanisms by which chronic consumption of alcohol predispose to cerebrovascular abnormalities, including stroke, however, are not clear. The studies proposed in this application will determine the effects of chronic alcohol consumption on the cerebral microcirculation. The central hypothesis of this application is that chronic alcohol consumption predisposes to cerebrovascular abnormalities by altering cellular processes which modulate reactivity of cerebral blood vessels. To examine this central hypothesis, we will conduct two series of experiments. The first series of experiments will examine the temporal effect of chronic alcohol consumption on important cellular signaling pathways (nitric oxide synthase, ATP-sensitive potassium channels and adenylate cyclase which produce dilatation of cerebral arterioles. We will also determine the mechanisms which may account for impaired dilatation of cerebral arterioles during chronic alcohol consumption and examine the morphology of cerebral arterioles. The second series of experiments will examine the temporal effect of chronic alcohol consumption on the distribution of microvascular pressure in the cerebral circulation. We will examine the distribution of cerebral microvascular pressure under basal conditions and during changes in arterial pressure. We believe that these studies will provide the first comprehensive examination of the effects of chronic alcohol consumption on the cerebral microcirculation and will provide valuable insights into factors which contribute to the pathogenesis of cerebrovascular abnormalities, possibly ischemic and hemorrhagic stroke, during chronic alcohol consumption.
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